1. Field of the Invention
The present invention relates to the field of treatment of neoplastic diseases and uncontrolled cell growth. More specifically, it relates to compositions and methods for treating tumors or cancers with combinations of a substance that activates a signalling pathway involving SHP-1, Syk, or both, and an anti-neoplastic agent that binds to a cell surface protein, such as a substance that binds CD33 molecules on the surface of neoplastic cells.
2. Description of Related Art
Neoplastic diseases, or cancers, are a leading cause of death in the world. Neoplastic diseases have been classified using various different schemes. One useful scheme differentiates the diseases based on the types of cells involved: solid tumors (which originate from cells of any tissue other than blood, bone marrow, or the lymphatic system) and non-solid tumors (which include cancers of the blood, bone marrow, and lymphatic system, such as leukemias and lymphomas).
Solid tumors can be of numerous types, each derived from a cell of a tissue of the body. On the other hand, non-solid tumors are of a limited type, due to the limited number of cell types in blood, bone marrow, and the lymphatic system. Leukemias are likely the most devastating type of non-solid tumor because they strike young children at a high rate and are particularly difficult to treat. Leukemias can be divided into two types: acute and chronic. Acute leukemias are leukemias of undifferentiated cells, whereas chronic leukemias contain mature, differentiated cells. Acute leukemias can be of two types: 1) lymphoblastic (ALL) and 2) non-lymphoblastic (ANLL), which is also known as acute myeloblastic leukemia or acute myeloid leukemia (AML). Chronic leukemias can also be of two types: 1) lymphocytic (CLL) and 2) myelocytic or myeloid (CML).
Numerous ways of treating neoplastic diseases have been developed over the years. The treatment of choice is typically surgery to remove the tumor because this type of treatment shows a high rate of success and is minimally damaging to unaffected cells of the body. However, many cancers do not lend themselves to surgery, and thus require alternative methods of treatment. Generally, non-surgical treatments include administering to the patient substances that are cytotoxic, and thus cause cell death (i.e., administering chemotherapeutic agents), exposure to cell-killing amounts of radiation, or both. The crudest treatments with cytotoxic agents use substances that do not differentiate between normal and neoplastic cells. Thus, while cancer cells are killed by the treatment, normal, healthy cells are killed as well. As the field of cancer treatment has evolved, the substances used for treatment have become more selective, being targeted only to growing cells or cells with proteins on their surfaces that are specific for cancer cells.
Because non-solid cancers are not confined to any single area of the body, treatment with surgery or radiation is not practical as the sole method of treatment. Likewise, because systemic killing of all cells of the body is undesirable, cytotoxic agents to be used in treating non-solid tumors should specifically target the cancer cells while avoiding non-cancer cells. Antibodies that are specific for cell-surface proteins that are typically expressed on cancer cells, but not normal cells, are particularly well suited for treatment of non-solid tumors. Indeed, it has been found that antibodies to the surface protein CD33, which is expressed on most myeloid leukemia cells, can be effective in treating this type of leukemia. Antibodies against CD33 are also attractive as therapeutic agents because it has been reported that the CD33 molecule is not expressed on the surface of normal hematopoietic stem cells, thus allowing for killing of cancerous cells while sparing the cells needed for repopulation of the bone marrow and the blood system.
To further improve the killing effectiveness of antibodies for non-solid tumor cells, various cytotoxic agents have been conjugated to antibodies that specifically bind the non-solid tumor cells. Such immunoconjugates or immunotoxins have proven to be effective in treating non-solid tumors. For example, a monoclonal antibody-chalicheamicin immunoconjugate (Mylotarg®, Wyeth, Madison, N.J.) that specifically binds CD33 has been approved by the FDA for first recurrence of AML. Other immunoconjugates, specific for CD33 or other cell-surface proteins on leukemia cells, have also been disclosed as effective.
For example, U.S. Pat. No. 6,759,045 to Goldenberg et al. discloses that naked anti-NCA90 antibodies or anti-NCA33 immunotoxins or immunoconjugates can be used to treat CML and AML. This patent discloses that the antibodies can be used alone or in combination with other substances, such as agents that induce expression of target molecules (e.g., expression of NCA-90). The patent also discloses that the antibodies can be used in conjunction with chemotherapeutic agents, such as daunorubicin, cytarabine, 6-thioguanine, etoposide, mitoxantrone, diaziquone, idarubicin, and others.
In addition, U.S. Pat. No. 6,007,814 to Scheinberg discloses mouse antibodies (M195) and fragments that are specific for CD33. It also discloses that such antibodies can be used to treat and diagnose leukemia in human patients. The antibodies can be used alone or in the form of immunoconjugates with toxins (immunotoxins). The patent discloses that this mouse antibody was administered to ten human patients, and that administration led to delivery of the M195 antibody to leukemia cells, but additionally resulted in an immune reaction against the M195 antibody (human anti-murine antibody response; HAMA). The patent further discloses that the M195 antibody was used in trials on patients who had previously failed to respond to certain chemotherapeutic agents or combinations of chemotherapeutic agents, such as idarubicin (IDA), cytosine arabinoside (Ara-C), mitoxantrone; hydroxyurea, daunomycin, and VP-16. However, due largely to the HAMA reaction, this antibody and human therapies involving this antibody have not been found to be clinically useful.
A recent study by the inventors showed a correlation between the presence of the protein kinase Syk in AML cells and anti-CD33 antibody growth inhibition of AML cells. (Balaian, L. et al., 2003.) The study showed that about one-half of AML cells are susceptible to growth inhibition and apoptosis-mediated cell death as a result of CD33 ligation by anti-CD33 antibodies, while about one-half are unresponsive to such anti-CD33 antibody treatment. That study also presented data consistent with the proposition that the Syk protein kinase is a tumor suppressor, and that lack of the protein itself, or perhaps functional Syk protein, is associated with resistance to inhibition and apoptosis-mediated cell death resulting from CD33 ligation. The authors postulated that determination of Syk expression level and/or functional activity of a patient prior to therapy could be useful in prognosing response of the patient to anti-CD33 mAb treatment. They also speculate that modulation of Syk expression could be a mechanism for increasing the efficacy of anti-CD33 mAb treatment.
MYLOTARG® (gemtuzumab ozogamicin; GO) is an anti-CD33 immunotoxin formed from the chemical conjugation of a recombinant humanized monoclonal mouse antibody (hP67.6) and calicheamicin, a potent bacterial toxin. In the immunotoxin, two to three calicheamicin molecules are chemically conjugated with the CD33 monoclonal antibody. Mylotarg was the first immunotoxin to be approved by FDA, and the first drug specifically approved to treat relapsed acute myelogenic leukemia (AML). Mylotarg is thought to be particularly well suited for treatment of AML because CD33 is expressed by leukemic blast cells and immature cells of myelomonocytic origin and other bone marrow hematopoietic cells, but not on normal pluripotent progenitor (stem) cells.
Although numerous studies have shown the effectiveness or potential effectiveness of antibodies and immunoconjugates as treatment agents for neoplasias, including non-solid tumors, because a certain portion of cells of a given neoplasia typically do not express a selected target protein on their cell surfaces, or are otherwise refractory to treatment with such agents, treatments using antibodies or immunoconjugates are not 100% effective. Thus, there exists a need in the art to improve the killing efficacy of antibodies and immunoconjugates.